Inherited disorders resulting from defective responses to DNA double strand breaks feature immunodeficiency, bone marrow failure, lymphoid malignancies and developmental delay. Cellular responses to double strand breaks require rapid communication between specialized DNA damage recognition complexes and the core cell cycle machinery, but this important relationship is poorly understood. In the previous project period we identified an unanticipated protein interaction that provides a unique opportunity to make major strides in understanding this relationship. The interaction involves Mre11, a core component of the DNA damage recognition machinery that is mutated in ataxia-telangiectasia like disorders (ATLD), and cyclin dependent kinase 2 (CDK2), a core component of the cell cycle machinery. We reported that the interaction facilitates CDK2 dependent phosphorylation of a single substrate, demonstrating for the first time that Mre11 has roles in the normal cell cycle. In this proposal we present preliminary evidence that Mre11 controls CDK2 functions more globally during the normal cell cycle. Our findings indicate that this control plays an important role when cells undergo DNA damage. Therefore, we will test the overarching hypothesis that Mre11 interacts with and controls CDK2 to provide a rapid switch between the normal cell cycle and the DNA damage response. We will determine roles that Mre11-CDK2 interaction plays is diverse biological contexts such as specialized recombination in lymphocyte development, and S phase checkpoint responses more generally. The studies proposed herein take advantage of murine systems with alleles of Mre11 that we constructed in the previous two project periods, along with new mouse models we will develop to directly test our hypotheses. The combination of our long term investment in the development of unique biological reagents and our discovery of Mre11-CDK2 interaction places the Principle Investigator's laboratory in a unique position to make major strides in our understanding of cellular responses to DNA damage and their associated diseases.